3-oxygenated-5alpha-androstane-2,17-diones



United States Patent M 3,128,293 3-0XYGENATED-5a-ANDROSTANE-2,17-DIONESPaul D. Klimstra, Northbrook, Ill., assignor to G. D. Searle & Co.,Chicago, IlL, a corporation of Delaware No Drawing. Filed Oct. 4, 1962,Ser. No. 228,268 Claims. (Cl. 260-3974) The present invention relates toa group of 3-oxygenated derivatives of 5a-androstane-2,17-dione. Moreparticularly, it relates to compounds of the following structuralformula ROM wherein R represents hydrogen, methyl, or lower alkanoyl.The lower alkanoyl radicals referred to above contain up to six carbonatoms and are exemplified by radicals such as acetyl, propionyl, andbutyryl.

Starting materials used for the preparation of the compounds of thepresent invention are the 2,3-epoxy-5u-androstan-i7-ones. If the25,3,8-epoxide is heated with a lower alkanoic acid, the corresponding3a-(lower alkanoyl)oxy-Zfi-hydroxy-Sot-androstan-17-one is obtained,while if the same epoxide is treated with methanol in the presence of atrace of acid, 2fl-hydroxy-3 ot-IIlCtl'lOXY-Sot-EUJ- drostan-l7-one isobtained. Oxidation of either of these Z/R-hydroxy compounds withchromium trioxide in sulfuric acid gives the corresponding5a-androstane-2,17- dione. These diones can be epimerized to thecorresponding 3p-=(lower alkanoyl)oxy or 313-111Cth0XY-5u-2111dt0-stane-2,l7 diones. The 3-(lower alkanoyl)-oxy compounds can be convertedto the corresponding 3-hydroxy- 5a-androstane-2,l7-dione by acidic orbasic hydrolysis or by alcoholysis with methanol.

If 2a,3a-epoxy-5ot-audrostan-17-one is treated with boron trifiuoride,3fi-hydroxy-5a-androstane-2,l7-dione is obtained. This compound can bemethylated with dimethyl sulfate to give the corresponding 3 fi-methoxycompound, or it can be esterified by means of the appropriate loweralkanoyl halide or lower alkanoic acid anhydride to give thecorresponding 3B-(lower alkanoy1)oxy-5a-androstane-2,l7-di0ne.

The compounds of the present invention are useful because of theirvaluable pharmacological properties. In particular, the 3a-oxygenatedcompounds of the present invention, in addition to being useful asintermediates for the preparation of the corresponding 3;i-compounds,are also anti-estrogenic agents as is evidenced by their ability toinhibit estrogen-stimulated biological responses. The B S-oxygenatedcompounds of the present invention possess hormonal properties as isevidenced by their androgenic activity.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only, and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples, temperaturesare given in degrees centigrade C.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

3,128,293 Patented Apr. 7, 1964 Example 1 A solution of 0.1 part offreshly distilled boron trifluoride etherate, 10 parts of2a,3a-epoxy-5a-androstane-17- one, and 44 parts of dimethyl sulfoxide isheated on the steam bathfor 3 hours. An additional 0.05 part of borontrifiuoride ethereate is added and heating is continued for anadditional 60 hours. The resulting solution is poured into water andextracted with 3 portions of chloroform. The combined chloroformextracts are washed twice with water and dried over anhydous potassiumcarbonate and charcoal. Evaporation of the'solvent gives a brown oilwhich is then dissolved in benzene and chromatographed on a silica gelcolumn. Elution with a 20% solution of ethyl acetate in benzene gives,after evaporation of the solvent and recrystallization from a mixture ofacetone and hexane, 3/3-hydroxy-Sa-androstane-Z,17-dione, melting atabout 164-167 C.; [a] =+108.5 (chloroform). This compound has thefollowing formula Example 2 A solution of 1.5 parts of2p,3fi-epoxy-5a-androstan-l7-' one in 16 parts of methanol containing0.1 part of concen trated sulfuric acid is refluxed on a steam bath for4 hours. The resultant mixture is poured into parts of ice water and theprecipitate which forms is separated, washed with Water, and dried.Recrystallization of this solid from a mixture of acetone and hexanegives 3a-methoxy-2 8-hydroxy-5u-androstan-17-one, melting at about172-173 C.; [a] =+101 (chloroform).

To a solution of 0.4 part of 3a-methoxy-2B-hydroxy-5aandrostan-17-one in18 parts of acetone is added portionwise, with stirring at roomtemperature, an aqueous solution which is 8 N in chromium trioxide and 8N in sulfuric acid until the brown color persists. The excess chromiumtrioxide is destroyed by the addition of 2 drops of 2-propanol.Inorganic salts are removed from the solution by filtration. Water isthen added portionwise to the filtrate until the solution becomesturbid. The mixture is then cooled, whereupon a solid precipitates andis filtered off. This product is 3a-methOXy-Sa-andrOstane-Z,17-dione,melting at about 163-1635 C. It has the following formula O H! I Example3 A solution of 5 parts of 25,3B-epoxy-5aandrostan-17- one and 130 partsof glacial acetic acid is heated on a steam bath for 4.5 hours. Themixture is then allowed to stand at room temperature for 15 hours beforeit is poured into ice water. The resultant mixture is extracted withether and the combined ether extracts are washed first with water andthen 15% sodium bicarbonate solution and finally dried over anhydrouspotassium carbonate and charcoal. The solvent is removed under reducedpressure and the residue is dissolved in benzene and chromatographed ona silica gel column. Elution of the column with a 10% solution of ethylacetate in benzene gives, after evaporation of the solvent andrecrystallization of the residual solid from a mixture of acetone andhexane, 3ix-acetoxy-2/3-hydroxy-5a-androstan-l7-one, melting at aboutl90192 C.; [a] =+l07.5 (chloroform).

An aqueous solution which is 8 N in chromium trioxide and 8N in sulfuricacid is added portionwise to a solution of 2 parts of3cc-acetoxy-Zfl-hydroxy-5a-androstane- 17-one in 28 parts of acetoneuntil the brown color persists. Excess chromium trioxide is destroyed bythe addition of isopropyl alcohol. The liquid which is decanted from thesalts which percipitated is poured into ice water. A precipitate forms;this is collected, washed with water, dried and then recrystallized froma mixture of acetone and hexane to give3a-acetoxy-5a-androstane-2,l7-dione, melting at about 155--l56 C.; [u]=+37.5 (chloroform). This compound has the following formula Example 4 Asolution of 0.3 part of 3a-acetoxy-5a-androstane- 2,17-dione and 0.8part of potassium acetate in 12 parts of glacial acetic acid is refluxedfor 5 hours. The resultant solution is poured into 80 parts of water.The precipitate which forms is separated, washed with water, and dried.This product is 3B-acetoxy-Sa-andrestane-Z,17-

dione, melting at about 182-184 C.; [u] =l140 (chloroform) 0 CH3 IIExample 5 l 5u-androstane-2,l7 dione. If this diketone is heated withpropionic acid and the product is isolated from the reaction mixtureaccording to the procedure described in Example 4, there is obtained3fi-propionoxy-5u-androstane-2,17-dione. This compound has the followingformula wherein R is selected from the group consisting of hydrogen,methyl, and lower alkanoyl.

2. A compound of the formula (lower alkanoyD-O E 3.3a-Acetoxy-Sa-androstane-Z,17-dione. 4. A compound of the formula (loweralkanoyl) -O l 5. BB-Acetoxy-Sa-androstane-Z,17-dione.

No references cited.

1. A COMPOUND OF THE FORMULA